rs587781056

Positions:

• chr16-15724796-G-A
• chrNT_187607.1-1382807-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_002474.3(MYH11):​c.3967C>T​(p.Leu1323=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0291 in 1,613,774 control chromosomes in the GnomAD database, including 2,817 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (1387 hom., cov: 32)
  • Exomes 𝑓: 0.023 (1430 hom.)
• Consequence: MYH11 NM_002474.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 5.90

Genes affected

MYH11 (HGNC:7569): (myosin heavy chain 11) The protein encoded by this gene is a smooth muscle myosin belonging to the myosin heavy chain family. The gene product is a subunit of a hexameric protein that consists of two heavy chain subunits and two pairs of non-identical light chain subunits. It functions as a major contractile protein, converting chemical energy into mechanical energy through the hydrolysis of ATP. A chromosomal rearrangement involving this gene is associated with acute myeloid leukemia of the M4Eo subtype. Mutations in this gene are associated with visceral myopathy, megacystis-microcolon-intestinal hypoperistalsis syndrome 2, and familial thoracic aortic aneurysm 4. [provided by RefSeq, May 2022]

NDE1 (HGNC:17619): (nudE neurodevelopment protein 1) This gene encodes a member of the nuclear distribution E (NudE) family of proteins. The encoded protein is localized at the centrosome and interacts with other centrosome components as part of a multiprotein complex that regulates dynein function. This protein plays an essential role in microtubule organization, mitosis and neuronal migration. Mutations in this gene cause lissencephaly 4, a disorder characterized by lissencephaly, severe brain atrophy, microcephaly, and severe cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 16-15724796-G-A is Benign according to our data. Variant chr16-15724796-G-A is described in ClinVar as [Benign]. Clinvar id is 138338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-15724796-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.248 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYH11	NM_002474.3	c.3967C>T	p.Leu1323=	synonymous_variant	30/41	ENST00000300036.6	NP_002465.1
MYH11	NM_001040113.2	c.3988C>T	p.Leu1330=	synonymous_variant	31/43	ENST00000452625.7	NP_001035202.1
NDE1	NM_017668.3	c.*545G>A		3_prime_UTR_variant	9/9	ENST00000396354.6	NP_060138.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYH11	ENST00000300036.6	c.3967C>T	p.Leu1323=	synonymous_variant	30/41	1	NM_002474.3	ENSP00000300036	P3
MYH11	ENST00000452625.7	c.3988C>T	p.Leu1330=	synonymous_variant	31/43	1	NM_001040113.2	ENSP00000407821
NDE1	ENST00000396354.6	c.*545G>A		3_prime_UTR_variant	9/9	1	NM_017668.3	ENSP00000379642	P1

Frequencies

GnomAD3 genomes AF: 0.0845 AC: 12856 AN: 152060 Hom.: 1387 Cov.: 32

Gnomad AFR AF: 0.252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0370

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.0346

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.0330

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0149

Gnomad OTH AF: 0.0593

GnomAD3 exomes AF: 0.0358 AC: 8994 AN: 251106 Hom.: 626 AF XY: 0.0320 AC XY: 4342 AN XY: 135740

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.0200

Gnomad ASJ exome AF: 0.0204

Gnomad EAS exome AF: 0.0278

Gnomad SAS exome AF: 0.0261

Gnomad FIN exome AF: 0.0314

Gnomad NFE exome AF: 0.0148

Gnomad OTH exome AF: 0.0287

GnomAD4 exome AF: 0.0233 AC: 34107 AN: 1461596 Hom.: 1430 Cov.: 34 AF XY: 0.0229 AC XY: 16657 AN XY: 727132

Gnomad4 AFR exome AF: 0.260

Gnomad4 AMR exome AF: 0.0227

Gnomad4 ASJ exome AF: 0.0214

Gnomad4 EAS exome AF: 0.0345

Gnomad4 SAS exome AF: 0.0270

Gnomad4 FIN exome AF: 0.0284

Gnomad4 NFE exome AF: 0.0147

Gnomad4 OTH exome AF: 0.0344

GnomAD4 genome AF: 0.0847 AC: 12883 AN: 152178 Hom.: 1387 Cov.: 32 AF XY: 0.0839 AC XY: 6242 AN XY: 74410

Gnomad4 AFR AF: 0.252

Gnomad4 AMR AF: 0.0368

Gnomad4 ASJ AF: 0.0216

Gnomad4 EAS AF: 0.0346

Gnomad4 SAS AF: 0.0195

Gnomad4 FIN AF: 0.0330

Gnomad4 NFE AF: 0.0149

Gnomad4 OTH AF: 0.0587

Alfa AF: 0.0329 Hom.: 433

Bravo AF: 0.0921

Asia WGS AF: 0.0400 AC: 139 AN: 3478

EpiCase AF: 0.0141

EpiControl AF: 0.0172

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 04, 2013	Leu1330Leu in exon 31 of MYH11: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 24.3% (1068/4394) of African American chromosomes from a broad population by the NHLBI Exome Seque ncing Project (http://evs.gs.washington.edu/EVS; dbSNP rs12907). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2018	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 07, 2015	General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Aortic aneurysm, familial thoracic 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 21, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Lissencephaly 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Lissencephaly, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 25, 2014

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.94
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs12907; hg19: chr16-15818653; COSMIC: COSV55546779; COSMIC: COSV55546779;